EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity.

Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide.